The present invention is directed to novel pyrroloquinoline alkaloids which demonstrate activity against bradykinin, .alpha.-adrenergic, histaminergic, and muscarinic receptors. Known bradykinin (BK) antagonists are peptides. The present invention describes an non-peptide that is a bradykinin antagonist. BK is a hormonal nonapeptide which mediates pain, vascular permeability, inflammation, gastrointestinal function, and smooth muscle tone in vascular and other tissues. BK is one of the key mediators of the body's response to trauma and injury. BK levels are generally low until a traumatic event triggers a cascade of biochemical reactions and a rise in the concentration of BK by proteolytic generation. High molecular weight precursors, the kininogens, are found in blood and tissue. This cascade is initiated by the activation of the Hageman factor which also initiates fibrinolysis and coagulation.
Receptors for BK exist in the nervous system, epithelia, smooth muscle and fibroblasts. In each tissue type BK triggers specific responses including neurotransmitter release, muscle contraction, fluid secretion by epithelia, and the stimulation of cell growth. The initial interaction for the biological response occurs at a BK receptor site on a cell. Specific peptide BK antagonists have been developed (Vavrek, Peptides, 6, 161-165 (1985)). Their potential use includes use as anti-nociceptive and anti-inflammatory agents. BK can activate neurons and produce neurotransmitter release. It activates phospholipases C and A.sub.2 resulting in the production of a number of bioactive intermediates including inositol triphosphate (Ins-1,4,5-P.sub.3), diacylglycerol(DAG) and arachidonic acid (AA) and its cyclooxygenase and lipooxygenase products. These substances cause cellular levels of cAMP, cGMP, and Ca.sup.2+ to increase. In neurons, the most important points of action for the substances released by BK stimulation may be ion channels, Miller, R. J., Trends Neurosci., 10, 266-228 (1987).
BK released during tissue damage causes vasodilation, increased vascular permeability, altered gut motility and pain. Specific BK receptors exist in intestinal mucosa and muscle. BK and its analogs stimulate Cl.sup.- secretion by the gut epithelia. BK has a contractile effect in muscle. Manning et al., Nature, 299, 256-259 (1982).
BK can open calcium channels as indicated by the inhibitory effects of Ca.sup.2+ channel blockers. Calcium may be involved in regulating BK receptor binding. See Innis et al., Proc. Natn. Acad. Sci., 2630-2634 (1981). BK also stimulates sodium intake and DNA synthesis. Owen et al., Cell, 32, 979-985 (1983).
Excessive kinin activity may play some role in carcinoid syndrome and in inflammatory bowel disease. Patients with ulcerative colitis have abnormally high levels of active kallikrein, the kinin-releasing enzyme, and plasma and tissue levels of peptidyl dipeptidase which degrades kinins are depressed in patients with regional enteritis. Manning et al., Nature, 299, 256-259 (1982).
The localization of BK receptors to nociceptive neurons supports a role for BK in pain mediation. Several BK antagonists block BK induced acute vascular pain in the rat. BK antagonists also relieve BK and unrate induced hyperalgesia in the rat paw. These results indicate that BK is a physiologic mediator of pain and that BK antagonists have analgesic activity in both acute and chronic pain models. The BK receptor involved in vascular pain may be different from the receptor involved in cutaneous hyperalgesia. Steranka et al., Proc. Natl. Acad. Sci. USA., 85, 3245-3249 (1988).
BK receptors have been classified as two major subtypes-.beta..sub.1 and .beta..sub.2. The BK metabolite des-Arg.sup.9 -bradykinin is a .beta..sub.1 receptor agonist which has higher potency than BK but it is relatively inactive at .beta..sub.2 receptors. Steranka et al., Proc. Natl. Acad. Sci. USA., 85, 3245-3249 (1988). BK receptors are G protein-coupled receptors that activate phospholipase C or phospholipase A.sub.2 and increases the synthesis of inositol triphosphate or arachidonic acid. Olsen et al., J. Bio. Chem. 263, 18030-18035 (1988). G-proteins are a family of membrane proteins that become activated only after binding guanosine triphosphate (GTP). Activated G-proteins in turn activate an amplifier enzyme on the inner face of a membrane; the enzyme then converts precursor molecules into second messengers. For example, an external signal molecule (bradykinin) may bind to its cell-surface receptor (BK-2) and induce a conformational change in the receptor. This change is transmitted through the cell membrane to a G-protein, making it able to bind to GTP. Binding of GTP causes another conformational change in the G-protein that enables it to activate phospholipases A.sub.2 and C. BK antagonists may be useful, therefore, to prevent the activation of G-proteins by bradykinin.
It is known that there is a large degree of heterogenicity within the muscarinic, adrenergic, and serotonergic classes of receptors. But, it is also known that "[s]imple classification of subtypes of BK receptors cannot fully account for the properties of these receptors on cells from a variety of tissues." Mahan et al., Mol. Pharmacol., 37, 785-789 (1990).
BK induces InsP formation through the activation of phosphatidylinositol-specific phospholipase C and subsequent mobilization of intracellular Ca.sup.2+ and activation of phospholipase A.sub.2, which causes the release of arachidonate and subsequent synthesis of prostaglandin E.sub.2 have been found to exist in Swiss albino mouse 3T3 cells and BALBc (SV-T2) mouse 3T3 cells and involve receptors coupled to pertussis toxin-insensitive G proteins. These receptors belong to the B.sub.2 subtype. Mahan et al., Mol. Pharmacol., 37, 785-789 (1990).
The effect of bradykinin on the neuroeffector junction of the isolated rat vas deferens has been studied. Llona et al., J. Pharmacol. Exp. Ther., 241, 608-614 (1987). BK potentiated the magnitude of the muscular response to the electrically driven twitches and contracted the smooth muscle generating an increased muscle tone. The former action is referred to as the neurogenic or presynaptic effect and the latter is called the musculotropic or postjunctional action. The rat vas deferens contains bradykinin receptors on the nerve endings and on smooth muscle membrane. The structural prerequisites for the activation of these receptor sites appear to be slightly different.
These results support the existence of B.sub.2 receptor subtypes. Des-Arg.sup.9 -BK and des-Arg.sup.9 -[Leu.sup.8 ]-BK are inactive in causing either pre- or postsynaptic BK like responses and incubation of des-Arg.sup.9 -[Leu.sup.8 ]-BK at high concentrations failed to antagonize BK responses in the vas deferens. This peptide is a known B.sub.1 antagonist. The authors suggest that there are several classes of BK-2 receptors. Llona et al., J. Pharmacol. Exp. Ther., 241, 613 (1987). See also Brass et al., Br. J. Pharmacol., 94, 3-5 (1988).
As indicated, BK mediates vasodilation, pain and smooth muscle contraction in a number of tissues. Many of these biological actions may result from the release of arachidonic acid and its metabolites. The major metabolite in Swiss 3T3 cells (fibroblasts) is PGE.sub.2 which induces smooth muscle contraction, mitogenesis, an increase in intracellular free calcium and stimulates adenylate cyclase(to produce cAMP). BK activates phospholipases which control intracellular arachidonate. Conklin et al., J. Pharmacol. Exp. Ther., 244, 646-649 (1988).
Phospholipases are considered to be the rate limiting enzymes in receptor mediated arachidonate release. BK activates PLA.sub.2, a phospholipase which cleaves arachidonic acid directly from the parent phospholipid. In contrast, BK in BPAE cells (bovine pulmonary artery endothelial cells) stimulates activity of a phosphatidylcholine-specific PLC which provides arachidonate substrate for PGI.sub.2 synthesis. The authors conclude that the BK receptors are pharmacologically distinct and that more BK subtypes exist beyond BK.sub.1 and BK.sub.2. Conklin et al., J. Pharmacol. Exp. Ther., 244, 646-649 (1988). To further clarify the role of bradykinin and express the need for an effective bradykinin antagonist, kinins are released in response to tissue injury and activate sensory pain fibers, contract venous smooth muscle and stimulate prostacyclin (PGI.sub.2) and endothelium derived relaxing factor (EDRF) synthesis. Blood flow to the damaged area and vascular permeability increase to cause inflammation. Plevin et al., Trends Pharmacol. Sci., 9, 387-389 (1988). Multiple .beta..sub.2 BK receptors in mammalian tissues are present. The tissues include guinea-pig ileum, vas deferens prejunctional, N1E-115 cells (neuronal cell line), rat uterus, and guinea-pig trachea (endothelial cells-BK linked to second messenger and coupled to a G-protein). There is a need, therefore, for a bradykinin antagonist which is useful in the treatment of a number of disorders in which bradykinin plays a role. Pharmacological agents containing guanidine moieties are known. See U.S. Pat. Nos. 5,059,624 and 5,028,613 describes tricyclic pyrroloquinoline alkaloids isolated and purfied from certain marine sponges which exhibit antitumor and antimicrobial activity. The instant invention, however, claims a novel pyrroloquinoline guanidine compound that is highly active as a bradykinin antagonist and is therefore useful to treat bradykinin associated disorders.